Family sitosterolemia: report of two cases in Colombia. / Sitosterolemia familiar: reporte de dos casos en Colombia.

Sitosterolemia is an autosomal recessive and very rare disease. Its main characteristic is that there is a greater absorption and a decrease in the excretion of sterols, which leads to them being deposited in tissues. It is given by mutations in the ABCG5 or ABCG8 genes found on chromosome 2p21. In this clinical note, we describe the first two patients with familial sitosterolemia described in Colombia, brothers, one of them with xanthomas in extremities as the only symptom, and the other, completely asymptomatic. Genetic studies were performed as a diagnostic test in both patients, where a pathogenic homozygous variant could be identified in the ABCG8 gene in the first case (symptomatic), and a heterozygous variant in the ABCG8 gene in the second case (asymptomatic); the first patient has responded to treatment with ezetimibe. In conclusion, xanthomas should be studied in depth in pediatric age as they may be the only visible sign of such complex and hereditary diseases as familial sitosterolemia, which can be controlled and prevent cardiovascular complications of the disease.

Widespread xanthomas regression by personalized lipid lowering therapy in heterozygous familial hypercholesterolemia.

"The lower, the better" is the recommended approach in the management of high LDL cholesterol. Unfortunately, this does not always achieve as in the case of a 69-year-old woman referred to our Institute for her lipid profile (LDL cholesterol 412mg/dl), bilateral xanthelasma and cutaneous xanthomas. With a maximized and personalized lipid-lowering therapies (rosuvastatin, ezetimibe, PCSK9i and lipoprotein apheresis), after only six months, the patient showed an impressive regression in her cutaneous xanthomas.

Factors associated with the presence of tendon xanthomas in familial hypercholesterolemia.

INTRODUCTION AND OBJECTIVES: Tendon xanthomas (TX) are lipid deposits highly specific to familial hypercholesterolemia (FH). However, there is significant variability in their presentation among FH patients, primarily due to largely unknown causes. Lipoprotein(a) is a well-established independent risk factor for atherosclerotic cardiovascular disease in the general population as well as in FH. Given the wide variability of lipoprotein(a) among FH individuals and the likelihood that TX may result from a proatherogenic and proinflammatory condition, the objective of this study was to analyze the size of TX in the Achilles tendons of FH participants and the variables associated with their presence, including lipoprotein(a) concentration. METHODS: A cross-sectional study was conducted on 377 participants with a molecular diagnosis of heterozygous FH. Achilles tendon maximum thickness (ATMT) was measured using ultrasonography with standardized equipment and procedures. Demographic variables and lipid profiles were collected. A multivariate linear regression model using a log-Gaussian approach was used to predict TX size. Classical cardiovascular risk factors and lipoprotein(a) were included as explanatory variables. RESULTS: The mean low-density lipoprotein cholesterol level was 277mg/dL without lipid-lowering treatment, and the median ATMT was 5.50mm. We demonstrated that age, sex, low-density lipoprotein cholesterol, and lipoprotein(a) were independently associated with ATMT. However, these 4 variables did not account for most the interindividual variability observed (R2=0.205). CONCLUSIONS: TX, a characteristic hallmark of FH, exhibit heterogeneity in their presentation. Interindividual variability can partially be explained by age, male sex, low-density lipoprotein cholesterol, and lipoprotein(a) but these factors account for only 20% of this heterogeneity.

Xantomas tuberosos en un paciente pediátrico: la clave en el diagnóstico precoz de una patología grave y poco frecuente / Tuberous xanthomas in a pediatric patient: a clue to the early diagnosis of a severe and infrequent disease

Los xantomas cutáneos reflejan el depósito de lípidos en la piel y pueden ser la única manifestación temprana de dislipidemias de inicio en la infancia. Las características y distribución de los xantomas orientan a la patología de base; los xantomas tuberosos tienen una fuerte asociación con la hipercolesterolemia homocigota familiar, una patología muy infrecuente. Su detección temprana otorga una ventana terapéutica para prevenir la ateroesclerosis acelerada y la mortalidad. Se presenta el caso de una paciente que comenzó a los dos años con xantomas tuberosos, que fueron la clave diagnóstica para identificar la hipercolesterolemia homocigota familiar subyacente.

Cutaneous xanthomas reflect lipid deposition on the skin and may be the only early manifestation of a childhoodonset dyslipidemia. Characteristics and distribution of the xanthomas signalize the underlying pathology, tuberousxanthomas being strongly associated with homozygous familial hypercholesterolaemia, an extremely rare condition. Its early detection provides a therapeutic window to prevent accelerated atherosclerosis and mortality. We present the case of a patient who started at two years with tuberous xanthomas, which were the diagnostic clue to identify the underlying homozygous familial hypercholesterolaemia.

Frequency and clinical and molecular aspects of familial hypercholesterolemia in an endocrinology unit in Ciudad Bolívar, Venezuela. / Frecuencia, aspectos clínicos y moleculares de la hipercolesterolemia familiar en una unidad de endocrinología de Ciudad Bolívar, Venezuela.

OBJECTIVE: To assess the frequency and the clinical, biochemical, and molecular aspects of familial hypercholesterolemia (FH) in subjects attending an endocrinology unit. METHODS: An observational, descriptive study evaluating 3,140 subjects attending the endocrinology unit of Centro Médico Orinoco in Ciudad Bolívar, Venezuela, from 7 January 2013 to 9 December 2016. The index cases were selected using the Dutch Lipid Clinic Network criteria. Plasma lipid levels were measured, and a molecular analysis was performed by DNA sequencing of the LDLR and APOB genes. RESULTS: Ten (0.32%) of the 3,140 study patients had clinical and biochemical characteristics consistent with FH. All but one were female. Three had first-degree relatives with prior premature coronary artery; and none had a personal history of this condition. Three patients were obese; three had high blood pressure; and no one suffered from diabetes. Three patients had a history of tendon xanthomas, and one of corneal arcus. LDL-C levels ranged from 191 to 486mg/dL. Two patients were on statin therapy. The genetic causes of FH were identified in four patients, and were LDLR gene mutations in three of them and an APOB gene mutation in exon 26 in the other. CONCLUSION: Approximately, one out of every 300 people attending this endocrinology unit in those four years had FH, and LDLR gene mutations were the most prevalent cause.

Hipercolesterolemia familiar descripción de un caso en una familia de Armenia - Quindío (Colombia)

Introducción: La Hipercolesterolemia familiar (HF) es una enfermedad genética de carácter autosómico dominante, poco frecuente, generada por la mutación en el cromosoma 19. Es la primera causa de enfermedad cardiovascular prematura. Las mutaciones patogénicas que generan la HF se relacionan con el receptor de LDL (LDLr), la apolipoproteina B-100 (Apo- B100) y la proteína convertasa subtilisina / kexina tipo 9 (PCSK9), que produce elevación del colesterol y alteración de la vía del LDLr en el 80 % de los casos diagnosticados de HF (5). Presentamos un reporte de caso de cuatro pacientes que pertenecen a la misma familia, quienes presentan mutaciones patogénicas de diferente compromiso a nivel cardiovascular y sistémico que ha afectado de manera negativa su cotidianidad. El objetivo de este trabajo es realizar una correlación del hipercolesterolemia familiar de tipo genético a partir de la literatura, con respecto a la serie de casos presentada, y evaluar el impacto que este genera en los servicios de salud, en la vida del paciente y su familia. Discusión: El reporte de caso que presentamos se fundamenta en la sospecha de HF según los criterios de Holanda. En estos pacientes se reconoce mutación del gen LDLr que se relaciona con HF. Sin embargo, no ha sido ampliamente estudiada. Chmara realizó en Polonia por primera vez un estudio en el que reportó la variante ac 11G>T. En Colombia, el estudio de López encontró tres mutaciones, identificadas como variante a c.11G > A, n c.416A > G y c.1187G > A (8). Conclusión: La HF en nuestro medio es poco frecuente y con gran impacto social, en la mayoría de los casos genera síntomas clínicos y aumento del riesgo cardiovascular desde una edad temprana. Es importante resaltar el diagnóstico oportuno y el conocimiento por parte del personal de salud para generar una calidad de vida adecuada a los pacientes y evitar que aumente el riesgo cardiovascular.

Introduction: Familial hypercholesterolemia (FH) is a rare autosomal dominant genetic disease caused by a chromosome 19 mutation. It is the main cause of premature cardiovascular disease. Pathogenic mutations which cause FH are related to the LDL receptor (LDLr), B-100 apolipoprotein (Apo-B100) and type 9 subtilisin/kexin convertase protein (PCSK9), causing blood cholesterol increase and impairment of the LDLr pathway in up to 80% of patients diagnosed with FH. We present the case of 4 patients belonging to the same family and who present pathogenic mutations leading to diverse kinds of cardiovascular and systemic disease. Discussion: The case report we are presenting is based on the suspicion of FH according to the dutch criteria. These patients had the LDLr gene mutation related to FH. However, this mutation has not been thoroughly studied. The ac 11G>T variant was reported for the first time in Poland by Chmara. In Colombia, Lopez found 3 mutations identified as variant a c.11G > A, variant n c.416A > G and variant c.1187G > A. Conclusion: FH is rare in Colombia. Early diagnosis and healthcare worker awareness must be highlighted to improve the quality of life and decrease the cardiovascular risk of patients.

Enfermedad de Erdheim-Chester: Serie de diecinueve casos y un diagnóstico diferencial de relevancia / Erdheim-Chester Disease: Series of nineteen cases and a relevant differential diagnosis

La enfermedad de Erdheim-Chester (EEC) es una histiocitosis de células no Langerhans de presentación proteiforme y escaso conocimiento. Se presenta una serie de 19 casos de 4 centros, registrados de junio de 2012 a junio de 2019. Se incluyeron aquellos pacientes con clínica, anatomía patológica e inmunohistoquímica característica de la enfermedad. Se excluyeron pacientes con hallazgos indefinidos. Resultados: al igual que en la literatura, el compromiso más frecuente fue el óseo por imagenología, la mitad de estos sintomático. Nuestra serie presenta mayor incidencia de mujeres (casi 70%). Siete pacientes presentaron nódulo mamario como forma de presentación. La mayoría recibieron dosis media de esteroides asociado a otra droga inmunosupresora. La mortalidad fue del 16%. Conclusión: comunicamos una serie de pacientes con la EEC mencionando las características más destacables. Es llamativo el número de pacientes con afectación mamaria, por lo cual proponemos téngase en cuenta en el diagnóstico diferencial de la patología tumoral mamaria.

Erdheim-Chester disease (ECD) is a non-Langerhans histiocytosis, protein manifestations at start and little known. We included 19 patients from June 2012 to June of 2019. Inclusion criteria: clinical features, histopathology and immunostaining compatible with ECD. We excluded patients with undefined features. Results: Bones were the most frequent affected, half of them were asymptomatic. Seventy per cent of the patients were women, and 7 of them developed a nodule breast as first manifestation of ECD. The patients were treated with corticosteroids associated or not with immunosuppressants. The mortality rate was 16%. Conclusion: We reported a series of patients with ECD, enhancing the most frequent features. It is striking the number of patients with breast involvement; we propose to include the Erdheim-Chester disease in differential diagnosis of breast tumor.

Xantomas, la pieza clave para el diagnóstico de una hipertrigliceridemia grave / Xanthomas, the key piece for the diagnosis of a severe hypertriglyceridemia

Resumen La hipertrigliceridemia grave es una entidad poco común que presenta complicaciones que varían desde xantomas eruptivos y lipemia retinalis hasta pancreatitis, la cual puede llegar a ser mortal. No hay valores absolutos de niveles de triglicéridos con los que los pacientes desarrollen complicaciones, por lo que es difícil determinar la necesidad de manejo intrahospitalario en pacientes asintomáticos. Presentamos el caso de un paciente de 47 años con hipertrigliceridemia grave, quien como único signo clínico presentaba xantomas generalizados. Se realiza una discusión del tema y revisión de la literatura.

Abstract Severe hypertriglyceridemia is a rare entity that presents complications ranging from eruptive xanthomas and lipemia retinalis to pancreatitis, which can be fatal. There are no absolute values of triglyceride levels with which patients develop complications, so it is difficult to determine the need for in-hospital management in asymptomatic patients. We present the case of a 47-year-old patient with severe hypertriglyceridemia, who presented generalized xanthomas as the only clinical sign. A discussion of the topic and review of the literature is made.

Hipercolesterolemia familiar heterocigota: Revisión de las estrategias para su identificación y detección sistemática / Heterozygous familial hypercholesterolemia: Review strategies for identification and screening / Hipercolesterolemia familiar heterozigótica: Revisão das estratégias para sua identificação e detecção sistemática

La hipercolesterolemia familiar heterocigota (HFHe) es una enfermedad genética, común, autosómica dominante, causante de enfermedad cardíaca coronaria precoz. Si la HFHe es detectada y tratada en forma temprana, aquellos individuos afectados llegan a tener una expectativa de vida equivalente a las personas no afectadas. Diferentes estrategias existen para realizar una correcta identificación de los casos con HFHe; criterios fenotípicos, basados en niveles elevados de colesterol de lipoproteínas de baja densidad (C-LDL), estigmas clínicos (arco corneal, xantomas), sumados a antecedentes familiares de elevación del C-LDL y eventos cardiovasculares precoces son clásicamente utilizados en la práctica diaria. Por otro lado, existe la posibilidad de hacer diagnóstico genético de la HFHe y complementarlo con los aspectos y criterios fenotípicos. El desafío, una vez identificado el caso de HFHe, es implementar una estrategia de detección familiar, ya que por las características de heredabilidad mencionadas de la enfermedad, existe un cincuenta por ciento de probabilidad que un familiar directo padezca la enfermedad. El objetivo principal de esta revisión es presentar y discutir las diferentes estrategias de identificación y detección de pacientes con HFHe.

Heterozygous familial hypercholesterolemia (HeFH) is a common autosomal dominant genetic disease, which causes premature coronary heart disease. If HeFH detected and treated early, those affected individuals have a life expectation equivalent to unaffected individuals. Different strategies exist to make a correct identification of cases with HeFH; phenotypic criteria, based on elevated levels of low density lipoprotein cholesterol (LDL-C), clinical stigmata (corneal arcus, xanthomas), together with a family history of elevated LDL-C and early cardiovascular events are conventionally used in daily practice. On the other hand there is the possibility of genetic diagnosis of HeFH and this is complemented with aspects and phenotypic criteria. Once identified HeFH case, the challenge is to implement a strategy of family screening, since the characteristics mentioned heritability of the disease, there is a fifty percent chance that a direct family member has the disease. The primary objective of this review is to present and discuss different strategies for the identification and detection of patients with HeFH.

A hipercolesterolemia familiar heterozigótica (HFHe) é uma doença genética comum, autossômica dominante, que causa a doença arterial coronariana precoce. Se HFHe é detectada e tratada precocemente, aqueles indivíduos afetados têm uma expectativa de vida equivalente a indivíduos não afetados. Existem diferentes estratégias para a identificação correta de casos com HFHe; critérios fenotípicos, baseados em níveis elevados de colesterol de lipoproteína de baixa densidade (C-LDL), estigmas clínicos (arco corneal, xantomas), juntamente com uma história familiar de elevados níveis de C-LDL e os eventos cardiovasculares precoces são convencionalmente utilizados na prática diária. Por outro lado, existe a possibilidade de realizar um diagnóstico genético da HFHe e esta é complementado com aspectos e critérios fenotípicos. Uma vez identificado o caso de HFHe, o desafio é implementar uma estratégia de triagem familiar, de acordo com as características mencionadas da hereditariedade da doença, existe uma chance de cinquenta por cento que um membro direto da família tem a doença. O principal objetivo desta revisão é apresentar e discutir estratégias diferentes para a identificação e detecção dos pacientes com HFHe.

Xantomas eruptivos en un niño normolipémico / Eruptive xanthomas in a normolipemic child

Los xantomas eruptivos son una enfermedad cutánea poco frecuente en la infancia que pueden aparecer en el contexto de trastornos primarios o secundarios del metabolismo lipídico y en algunas ocasiones no se asocian a ninguna enfermedad de base. Presentamos el caso de un niño de tres años de edad con múltiples pápulas amarillentas en los párpados, el tronco y los miembros superiores desde los dos años de edad, sin alteraciones en su perfil lipídico, que coincidían con xantomas. Consideramos importante informar este caso y hacer una revisión del tema debido a su baja prevalencia.

Normolipemic eruptive xanthomas are a very rare skin disorder in children. They most often occur in the context of primary or secondary lipid metabolism disorders, but sometimes no systemic involvement or lipid disorder is found. We report a 3 year old boy with multiple yellowish papules on the eyelids, trunk and superior extremities since he was 2 years old, with a normal lipid profile. We consider it is important to report this case due to its low prevalence.

Xantomas eruptivos asociados a diabetes mellitus tipo II e hipertrigliceridemia: reporte de un caso / Eruptive xanthomas associated to diabetes mellitus type II and hypertriglyceridemia: a case report

Se reporta el caso de un hombre de raza blanca, 37 años de edad, hijo de madre con diabetes mellitus tipo 1, con antecedentes patológicos personales de padecer de obesidad exógena desde aproximadamente cinco años. Comenzó a presentar de forma diseminada una erupción papulosa de color amarillento, que se diagnosticó clínicamente e histológicamente como xantomas eruptivos asociados a diabetes mellitus tipo 2 de debut e hipertrigliceridemia. Se describen las generalidades de los xantomas eruptivos, sus formas de presentación, así como las características etiológicas e histopatológicas de la enfermedad.

The case of a white, 37 years old man is reported, his mother with diabetes mellitus type 1, with personal pathological antecedents of suffering exogenous obesity from approximately five years. He began to present in a disseminated form a papular eruption of yellowish color that was clinically and histological diagnosed like eruptive xantomas associated to diabetes mellitus type 2 appearing for the first time and hypertriglyceridemia. The generalities of the eruptive xantomas are described, their presentation forms, as well as the etiologic and histopathologic characteristic of the disease.

Xantomas eruptivos: A propósito de dos casos familiares / Eruptive xanthomas: Two familial clinical cases

Se presentan dos pacientes de sexo masculino, familiares de primer grado, tabaquistas y etilistas severos, sin antecedentes patológicos conocidos. Ambos presentan en forma eruptiva la aparición de xantomas y uno de ellos una pancreatitis necrohemorrágica atribuida a su hipertrigliceridemia, complicación muy grave de este trastorno. Si bien los xantomas eruptivos no son muy frecuentes de observar, deben hacernos sospechar en una dislipidemia severa, confirmándola con una examen de laboratorio que pondrá de manifiesto una elevación significativa de los triglicéridos y frecuentemente alteración de los niveles de glucosa en sangre. Además, el estudio histopatológico de las lesiones mostrará macrófagos cargados de lípidos, de aspecto espumoso e infiltrado polimorfonuclear y mononuclear en dermis.

We report a case of two male patients, first-grade relatives, who are heavy drinkers and smokers but apparently have no pathological records. Both show eruptive xanthomas and one of them presents acute necrotic and hemorrhagic pancreatitis due to hypertriglyceridemia, a serious complication of this disorder. Despite the fact that eruptive xanthomas are not frequently observed, they should make us suspect an instance of severe dyslipidemia. In order to verify it, a laboratory test will show a dramatic raise of serum triglyceride levels and usual changes in the blood glucose levels. Moreover, a histopathologic study of the lesion will reveal macrophages full of lipids (foam cells) with polymorphonuclear and mononuclear infiltrate.

Síndrome de Alagille: resolución de xantomas posterior a trasplante hépatico / Alagille Syndrome: resolution of xanthomas after liver transplantation

El síndrome de Alagille es uno de los desórdenes genéticos que, con mayor frecuencia, causan enfermedad hepática crónica en los niños. Se caracteriza por presentar colestasis durante el período neonatal la cual se manifiesta clínicamente a través de: ictericia, prurito y aparición de xantomas diseminados desde edades tempranas. Presentamos una niña con diagnóstico de síndrome de Alagille que requirió trasplante hepático por su enfermedad de base y describimos la evolución de los xantomas luego del mismo.

The Alagille syndrome is one of the most common inherited disorders causing chronic liver disease during childhood. Clinically, it is characterized by the presence of neonatal cholestasis. Cutaneous manifestations include jaundice, pruritus and widespread xanthomas during early childhood. We report a girl with Alagille syndrome diagnosis, who required liver transplantation and describe the evolution of the xanthomas after the hepatic transplantation.